Impaired TLR‐2 expression and TLR‐2‐mediated cytokine secretion in macrophages from patients with atopic dermatitis

Niebuhr, Margarete; Lutat, Carolin; Sigel, Stefanie; Werfel, Thomas

doi:10.1111/j.1398-9995.2009.02050.x

Cited by 72 publications

(62 citation statements)

References 34 publications

(29 reference statements)

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“…In atopic patients, TLR2 expression is downregulated in macrophages (22). Our study showed no decrease in keratinocytes of atopic or contact dermatitis, as we initially expected.…”

Section: Resultssupporting

confidence: 70%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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The aim of the study was to investigate the expression of Toll-like receptors (TLRs) 2 and 4 on keratinocytes in atopic dermatitis, contact dermatitis, and psoriasis by PCR and by immunohistochemistry including confocal microscopy. Confocal microscopy revealed a granular intra-cellular expression pattern for TLR 2 and a homogenous intra-cellular expression pattern for TLR 4 in normal and diseased skin. TLR 2 was constitutively expressed in the suprabasal layers in normal skin, but limited to the basal epidermis in diseased skin. TLR 4 expression was concentrated to the basal layers in normal skin, whereas it was pronounced in upper layers in diseased skin. The shift in the TLR expression may be related to the disturbed skin barrier and a need for enhanced immune surveillance because of invading microbes. Also, there must be a balance between sufficient immune response and overstimulation.Abbreviation: TLR, Toll-like receptor.

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“…In atopic patients, TLR2 expression is downregulated in macrophages (22). Our study showed no decrease in keratinocytes of atopic or contact dermatitis, as we initially expected.…”

Section: Resultssupporting

confidence: 70%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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“…Flow cytometric analysis was performed as described previously (15,33,34). Cells were washed and resuspended in phosphate-buffered saline (PBS) containing 0.2% gelatin, 20 mM sodium azide, and 10 g/ml heat-aggravated human immunoglobulin G (IgG) (Sigma, Deisenhofen, Germany) to block the Fc receptor (FcR) for 15 min.…”

Section: Isolation Of Monocytes and T Cells And Polarization And Expamentioning

confidence: 99%

Staphylococcal Alpha-Toxin Is a Strong Inducer of Interleukin-17 in Humans

et al. 2011

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Patients with atopic dermatitis (AD) are frequently colonized with Staphylococcus aureus, with one-third of isolates producing alpha-toxin. Moreover, S. aureus colonization is positively correlated with the severity of eczema. Interleukin-17A (IL-17A) has gained attention in diseases associated with chronic skin infections. The aim of this study was to investigate the effects of sublytic alpha-toxin concentrations on IL-17A production. Sublytic alpha-toxin concentrations strongly induced IL-17A in peripheral blood mononuclear cells (PBMCs), isolated CD4 ؉ T cells, polarized Th17 cells, and Th17 clones from reactive atopy patch test lesions and blood from AD patients. Alphatoxin induced IL-17A directly in T cells. The effect of alpha-toxin was further amplified by upregulation of IL-1 in monocytes. In conclusion, higher levels of IL-17A secretion induced by alpha-toxin in the skin partially explain how colonization with S. aureus can contribute to chronic skin inflammation.Atopic dermatitis (AD) and psoriasis (PS) are the most common immune-mediated chronic inflammatory skin diseases, with an increasing prevalence, affecting approximately 1 to 4% of the population in industrial countries (8,36,39). One hallmark of AD is a striking susceptibility to colonization with Staphylococcus aureus: 80 to 100% of patients with AD are colonized with S. aureus (4, 27). In contrast, S. aureus can be isolated from the skin of only 5 to 30% of healthy individuals, mainly from intertriginous areas (27). Moreover, a positive correlation between disease severity and extent and S. aureus colonization of lesional and nonlesional skin has been noted (4), which may be due to IgE-mediated hypersensitivity (3, 23) or to production of exotoxins with superantigenic properties (28,40,46). For PS, one study detected S. aureus in nonlesional skin of 27% of patients and in 46% of skin lesions (26). Tomi et al. investigated 25 PS patients: the skin of 60% of patients was positive for S. aureus, and isolated S. aureus strains were toxigenic, carrying staphylococcal enterotoxins A to D (SEA to SED), in 36% of patients. Furthermore, the PASI score correlated significantly with the presence of enterotoxinproducing S. aureus strains (43).Recently, the superantigen SEB was shown to enhance house dust mite-induced patch test reactions in patients with AD (20). Besides unspecific stimulation of T-cell receptor (TCR) V␤ chains, superantigens can augment an antigen-specific T-helper 1 (Th1) response via the induction of interleukin-12 (IL-12) in antigen-presenting cells (APCs), which might contribute to AD becoming chronic (7,22). On the other hand, the severity of AD decreased in patients colonized with nontoxigenic S. aureus strains upon antimicrobial treatment as well, which suggests the involvement of pathogenic factors other than superantigens derived from S. aureus (5).A distinct percentage of S. aureus strains are able to produce alpha-toxin, a potent 33-kDa cytolysin which does not belong to the group of enterotoxins (superantigens) (9). In a for...

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“…Dermal Mfs are expressing a wide range of MyD88-dependent TLRs to detect bacterial components like LPS or bacterial nucleic acids and to produce proinflammatory cytokines and chemokines (15,(17)(18)(19). Thus, they contribute to a healthy skin and immune cell homeostasis.…”

mentioning

confidence: 99%

MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection

Feuerstein

Seidl

Prinz

et al. 2015

The Journal of Immunology

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When Staphylococcus aureus penetrates the epidermis and reaches the dermis, polymorphonuclear leukocytes (PMLs) accumulate and an abscess is formed. However, the molecular mechanisms that orchestrate initiation and termination of inflammation in skin infection are incompletely understood. In human myeloid differentiation primary response gene 88 (MyD88) deficiency, staphylococcal skin and soft tissue infections are a leading and potentially life-threatening problem. In this study, we found that MyD88-dependent sensing of S. aureus by dermal macrophages (Mϕ) contributes to both timely escalation and termination of PML-mediated inflammation in a mouse model of staphylococcal skin infection. Mϕs were key to recruit PML within hours in response to staphylococci, irrespective of bacterial viability. In contrast with bone marrow–derived Mϕs, dermal Mϕs did not require UNC-93B or TLR2 for activation. Moreover, PMLs, once recruited, were highly activated in an MyD88-independent fashion, yet failed to clear the infection if Mϕs were missing or functionally impaired. In normal mice, clearance of the infection and contraction of the PML infiltrate were accompanied by expansion of resident Mϕs in a CCR2-dependent fashion. Thus, whereas monocytes were dispensable for the early immune response to staphylococci, they contributed to Mϕ renewal after the infection was overcome. Taken together, MyD88-dependent sensing of staphylococci by resident dermal Mϕs is key for a rapid and balanced immune response, and PMLs are dependent on intact Mϕ for full function. Renewal of resident Mϕs requires both local control of bacteria and inflammatory monocytes entering the skin.

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Impaired TLR‐2 expression and TLR‐2‐mediated cytokine secretion in macrophages from patients with atopic dermatitis

Abstract: Our findings clearly show an impaired TLR-2 expression and functional differences of TLR-2-mediated effects on macrophages of AD patients compared to healthy controls which might contribute to the enhanced susceptibility to skin infections with S. aureus in AD.

Cited by 72 publications

References 34 publications

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Staphylococcal Alpha-Toxin Is a Strong Inducer of Interleukin-17 in Humans

MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection

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